This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Heart failure is a leading cause of hospitalization and mortality. Cardiac hypertrophy, although considered an adaptive response to preserve cardiac function, increases the risk of heart failure. However, little is known about the mechanisms leading to heart failure in cardiac hypertrophy. The mammalian target of rapamycin (mTOR) is well known as a key downstream effector of insulin-like growth factor 1 (IGF-1), a cardioprotective growth factor. Studies with rapamycin suggest that mTOR inhibition prevents cardiac hypertrophy and preserves cardiac function in the acute phase of pathological hypertrophy. However, the role of cardiac mTOR has not been fully defined because of the existence of a rapamycin-insensitive mTOR complex. We have generated transgenic mice with cardiac-specific overexpression of mTOR driven by the [unreadable]MHC promoter (mTOR-Tg). In preliminary studies, we found that the mTOR-Tg mice were substantially protected against pressure overload induced-heart failure compared to littermate controls (NTg). These data suggest that mTOR is sufficient to protect the heart from heart failure in cardiac hypertrophy. Recent reports have demonstrated that angiogenesis plays an important role in cardiomyocyte survival during hypertrophy. In addition, it is known that mTOR increases VEGF expression in other tissues. The overall goal of the current proposal is to define the role of mTOR-induced angiogenesis in protecting the heart against heart failure following pathological hypertrophy. This proposal is based on the following hypotheses: 1) that mTOR is sufficient to prevent development of heart failure in cardiac hypertrophy;and 2) that angiogenesis enhanced by mTOR activation plays an important role in cell survival during cardiac hypertrophy. To test these hypotheses, we will study the following two aims. In Specific Aim 1, we will examine how mTOR mediates angiogenesis in the heart. We will examine cardiac angiogenesis in vivo mTOR-Tg mice and heterozygous mTOR-knockout (KO) mice at baseline. We will also examine mTOR-regulated angiogenic factors (especially VEGF) secreted from ex vivo perfused hearts (Langendorff) of mTOR-Tg and mTOR KO mice. In Specific Aim 2, we will evaluate the role of angiogenesis in mTOR-mediated cardiomyocyte survival and function in pressure overload-induced cardiac hypertrophy. Using adenoviral gene transfer (Ad), we will introduce a soluble protein consisting of the ligand-binding ectodomain of the VEGF receptor (Ad.Flk1) into mice to examine the effect of mTOR on survival and angiogenesis is dependent on the increase in VEGF activity. Understanding the effects of mTOR on angiogenesis in cardiac hypertrophy may provide novel therapeutic approaches for the management of heart failure in cardiac hypertrophy.